Cardiomyopathy in pediatric patients is life-threatening and may result from genetic
defects. While well established in adults, genetic mechanisms, early pathological
events, and other disease promoting factors are poorly characterized in children.
Recently, we identified pathogenic variants in the gene PR/SET domain 16 (PRDM16) underlying isolated cardiomyopathy in patients with nonsyndromic left ventricular
noncompaction cardiomyopathy (LVNC).
To further analyze the genetic burden and frequency of genetic variants in PRDM16, we screened pediatric and adult primary cardiomyopathy cohorts of 222 patients with
next-generation sequencing (Illumina TruSight Cardio Sequencing Panel). The cohort
included patients with dilated cardiomyopathy, hypertrophic cardiomyopathy, restricted
cardiomyopathy, LVNC, and arrhythmogenic right ventricular cardiomyopathy. Evaluation
of genetic variants in 89 cardiomyopathy-associated genes was performed after bioinformatic
filtering with a minor allele frequency of 0.1%. Case-specific interpretation of the
variants occurred in the familial and functional protein context according to the
American College of Medical Genetics and Genomics guidelines.
In total, we identified 14 heterozygous PRDM16 variants in patients from different pediatric and adult cohorts. Three of these variants
were classified as pathogenic, one was likely pathogenic and nine were VUS. More specifically,
three truncating variants c.1573dup, c.1627C>T, and c.2104A>T were detected that may
induce haploinsufficiency. One missense variant c.1110C>A localizes within the N-terminal
zinc finger region, which may affect its structural property. Surprisingly, genetic
variants in PRDM16 were frequent in our cohort as similar variant frequencies were observed for typical
cardiomyopathy genes such as DSP and TNNT2.
The phenotypes of the patients with PRDM16 variants included all five cardiomyopathies mentioned earlier, and therefore, PRDM16 is an important general cardiomyopathy gene. Interpretation of PRDM16 variants in the specific-disease context is restrained due to limited information
about the PRDM16 protein function. Thus, functional analysis of PRDM16 truncating and missense variants will provide further understanding into the underlying
disease mechanism.
